PROJECT SUMMARY/ABSTRACT In today?s efforts to personalize medicine, it does not seem reasonable to personalize medicine without constructing and utilizing an individual?s genome structure for both haplotypes. Current standards force the reference genome?s structure on each individual. The same principle applies to understanding the function for individual RNA isoforms. Structural variants are involved in, or directly cause, a broad range of diseases including cancer, autism, schizophrenia, neurodegenerative diseases, and Crohn?s disease, among others. We seek to better understand how structural variants affect disease by helping characterize structural variants and their downstream effects, combining this information with RNA isoform sequencing (IsoSeq). The histocompatibility complex, which contains the human leukocyte antigen (HLA) genes, is a particular region of interest for my lab because this region has been implicated in dozens of diseases. Similarly, we seek understand the role for individual RNA isoforms for all genes. Protein-coding human genes average seven RNA isoforms, resulting in unique protein products. For practical reasons, standard short-read RNA sequencing studies treat all isoforms as a single ?gene??an oversimplification of the underlying biology; this is also true when considering sex differences in human health and disease. While females and males have many similarities, both sexes have unique biology with clear differences in disease prevalence, therapeutic needs, and responses. Females, in particular, have not received adequate attention in human health and disease research. A next critical step in all of biology research, especially in disease research, will be to determine individual isoform function, and how that changes between sexes. We want to contribute to this effort, and propose to employ long-read sequencing technologies to accomplish these goals.